Discussion
In this novel study we analyzed the impact of pancreatic, cardiac, and
pituitary IO quantified in a cohort of pediatric cancer patients
evaluated for transfusional IO as part of their clinical care. The
results highlight the significant level of IO in some pediatric cancer
patients with the majority of patients in this cohort showing at least
moderate levels of IO ( LIC > 7 mg/g). Importantly, at
least 80% had evidence of extrahepatic iron loading (pancreas,
pituitary, heart) which implies significant exposure to the toxic,
reactive ferrous form of iron.11,23 The high
occurrence and magnitude of extrahepatic iron compared to a previous
cohort randomly sampled across diagnoses1 reflects
sample bias as subjects entered this cohort because their oncologists
had enough clinical concern to obtain iron studies. Hence, the diagnoses
in Table 1 are routinely treated with intense transfusion and
chemotherapy.
In addition to iron loading through transferrin receptor-mediated
processes and pathological loading via ion channels11,
the liver loads iron by reticuloendothelial ingestion of erythrocytes.
Thus, increase in LIC is linearly related to the number of transfusions
and can be considered a surrogate for transfusion volume in the absence
of chelation therapy or significant bleeding. In contrast, pathological
extrahepatic iron loading occurs only when circulating reactive ferrous
(Fe++) iron enters via divalent ion transporters
(Zn++ and Ca++) which are not
down-regulated by intracellular iron.11,24 The
reactive ferrous sub species of non-transferrin-bound iron (NTBI) is
referred to as labile plasma iron (LPI).
Normally, iron from senescent autologous or transfused RBC is recycled
and used to make new RBC. However, when erythropoiesis is suppressed
after cytotoxic chemotherapy, the iron binding ability of transferrin is
exceeded and levels of the NTBI and ferrous iron become very elevated
leading to unregulated transport of reactive iron into extrahepatic
sites.3,25,26 Thus, erythropoietic activity is a major
regulator of ferrous iron levels, iron toxicity, and distribution of
iron into endocrine organs and heart. Iron is only detectable by MRI
after it is converted to non-reactive ferric iron and stored as
aggregates of ferritin.27-29 Organ dysfunction does
correlate with the amount of extrahepatic iron detected by
MRI.11,22,30,31
This physiology is supported by numerous studies of iron loading,
extrahepatic iron distribution, end organ function and response to
chelation in individuals with chronic transfusion dependent anemia
associated with normal, ineffective, and no
erythropoiesis.32,33 The liver loads first and
independently of marrow activity, presumably because of the large
reticuloendothelial space and direct ingestion of
RBC.32 In the presence of high circulating NTBI/LPI,
the pancreas loads sooner than the heart.19 Presumably
the relative loading rates of the extrahepatic sites depends on
differing kinetics of ferrous iron transport in various divalent iron
transporters in different organs.
Patients treated for high-risk malignancies have often been exposed to
intensive chemotherapy that can transiently shut off erythropoiesis,
leading to prolonged exposure to elevated levels of NTBI/LPI due to the
absence of erythropoiesis, with NTBI/LPI levels subsequently decreasing
with marrow recovery as has been clearly shown during HSCT
conditioning3,26. Transferrin saturation, an indirect
measure of LPI,33 often increases to
>80% in HSCT even when the patient is not iron loaded at
the outset3,26 and is inversely related to
reticulocyte count.25,34
Most subjects (80%) had some level of pancreatic IO, and 16% had
levels in range that has been associated with glucose intolerance and
diabetes.35 Twenty-eight percent (8/29) of the
pituitary MRIs had siderosis and pancreatic siderosis was evident in all
those evaluated, consistent with prior studies of pituitary iron loading
in transfusion dependent anemia.22 Pituitary volume
loss has been associated with pituitary dysfunction in transfused
populations even in the absence of pituitary
siderosis,22 suggesting that LPI may cause damage even
before there is enough loading to be detected by MRI. However, in this
cohort, cranial radiation or chemotherapy likely affect pituitary volume
and function as well. Theoretically, oxidant damage from radiation or
chemotherapy will be markedly amplified by the presence of ferrous iron.
This is suggested by the 29-fold increased risk of second malignancy
when radiation is delivered with myelosuppressive
chemotherapy.36 Thus, we cannot exclude a possible
contribution of LPI to the volume loss seen in the brain tumor patients
even though there was no detectable iron in the pituitary (Figure 1).
This raises interesting questions regarding treatment timing and
delivery of radiation in proximity to marrow suppression when reactive
iron levels would be very high. These pituitary iron and volume changes
are particularly thought provoking considering that over 75% of
survivors of childhood cancer have pituitary dysfunction by 50 years of
age.37
Not surprisingly, there was no relation between treatment intensity
(ITR-3)13 and magnitude of IO or distribution of iron
loading in this cohort. This was likely due to insufficient variability
among the subjects as all were in the highest levels of the intensity
scale; further, this scale does not specifically consider magnitude and
duration of erythroid suppression. HSCT also did not influence iron
loading or distribution in this cohort, again likely due to the overall
higher intensity of treatment received by this cohort. Prior studies
indicate higher-intensity therapy, particularly HSCT, is associated with
higher transfusion burden and higher levels of NTBI, thereby increasing
risk of IO in both hepatic and extrahepatic
sites.38-40
While ferritin levels were obtained in this study and were often used by
the referring oncologists to screen for iron loading, the diagnosis of
IO was based on MRI determination of LIC. Ferritin levels do correlate
with LIC in large populations but the variability is very large making
single measurements not useful and even trends can be misleading with
ferritin trending upward when LIC is stable or
dropping.41 We used ferritin trends to optimize timing
of confirmatory MRI for assessment of tissue iron as this is the “gold
standard”, although ferritin can be used to infer iron burden in
resource restricted settings. We found ferritin over 800 ng/dl is 80%
predictive of a LIC >3 mg/g, consistent with data from
large populations of transfusion dependent anemia
patients,42-44 and confirmation with repeated
measurement should prompt MRI for verification of IO to more accurately
assess if iron removing therapy is needed. Transferrin saturation is
also highly variable, although in large epidemiological studies,
elevated transferrin alone predicts early death and higher probability
of malignancy.45 An elevated iron saturation,
>60% on several measures, indicates higher likelihood of
exposure to LPI, which increases risk of endocrine and cardiac iron
deposition, and utilization of chelation instead of or in addition to
phlebotomy should be considered. In fact, high pancreatic iron likely
prompted a number of subjects in this cohort to be treated with
chelation rather than phlebotomy (Figure 3B).
The primary and novel conclusion of this work is that there is
significant partitioning of iron into extrahepatic sites in a large
percent of pediatric patients after aggressive treatment for cancer.
This extrahepatic loading only occurs with significant exposure to the
highly reactive and toxic ferrous form of iron (LPI). The presence of
elevated LPI is caused by decreased marrow erythroid activity in the
face of multiple transfusions.
Strengths of this study include a diverse patient population with regard
to age and diagnosis, and the inclusion of initial and follow up MRI
evaluation of liver, pancreas, cardiac and pituitary, the last of which
is novel in this setting. Inclusion of all referred patients and
consistency in diagnostic approach are additional strengths. Limitations
include that this was an at-risk cohort specifically evaluated over
concern for possible IO. Thus, these results are generalizable to
children treated with higher-intensity cancer therapy and many PRBC
transfusions, but less so to childhood cancer patients as a whole. An
additional limitation was the inability to include PRBC transfusion data
due to variations in documentation over the study period.
The goal of this work is to protect cancer survivors from the toxicity
of iron over their lifespan. It is clear from work outside the oncology
realm that iron toxicity is primarily related to the amount of tissue
ferrous iron and the duration of exposure.23 This
means a small amount of iron over many decades can cause damage. As an
example, ineffective erythropoiesis with transfusion every three weeks
and no chelation in thalassemia leads to pituitary dysfunction in about
5 years, diabetes in about 10, heart failure and death in about 15 years
and increased cancer risk in the fourth and fifth
decade.35,46,47 It is also clear that reducing iron
can reverse endocrine failure and reduce risk of new cancers by 30%
even when iron is treated in the sixth decade.10,48
There are many interesting questions raised by this data regarding IO
and its incidence, prevalence, and relation to specific therapy in
malignancy. Critically, we need to know how much iron is in the body
after chemotherapy, and whether extrahepatic iron distribution is
present. This information can be obtained by a single abdominal MRI with
pancreas in the field. If the pancreas is positive, the heart and
pituitary should be assessed. Since we do not know how much
area-under-the-curve exposure to ferrous iron in childhood will cause
issues decades later, it seems prudent to eliminate measurable
pathologic iron as soon as is practical. Furthermore, measurable
toxicity occurs long after loading is detected and likely after the
patient leaves the pediatric environment. We think it is optimal that
pathological iron be addressed before the patient transitions from the
pediatric cancer treatment center. In addition to the magnitude and
distribution of loading, family understanding of the reasons for iron
removal, the likelihood that normalizing iron will reduce risk,
reassurance of the certainty of our ability to safely remove the
measurable iron, and design of a flexible approach that is acceptable to
the family are all critical considerations.
Conflict of Interest Statement: There is no conflict of interest to
disclose.
Acknowledgements: Nathan Smith, project manager at the Children’s
Hospital cancer and blood institute for his contribution with data
collection and organization and keeping the project on track.